Regulation of gene transcription is the primary process by which a cell controls the appropriate expression of the multitude of genes necessary for growth and differentiation. The selective expression of genes at appropriate times is highly specialized in cells of multicellular organisms and permits the cells to perform "housekeeping" functions and respond to changes in their environment. These changes involve extracellular signals from a variety of sources such as hormones, neurotransmitters, and growth and differentiation factors.
Gene transcription is controlled by proteins termed regulators of gene transcription (RGT). RGTs act by binding to a short segment of DNA (transcription control element, TCE) located near the site of transcription initiation. Binding of an RGT to the target TCE activates transcription of the gene. RGTs contain a variety of structural motifs that, alone or in combination with one another, permit them to recognize and bind to the wide variety of TCEs. Two motifs common to many RGTs are the Helix-Loop-Helix (HLH) and leucine zipper (LZ) motifs. These motifs are found in the large myc family of proteins that function in the control of normal cell growth and differentiation and in oncogenesis (Katzav, S. et al.(1991) Mol. Cell. Biol. 11:1912-20).
The HLH motif is found in the C-terminal portion of the RGT and is characterized by a short .alpha. helix. Connected by a flexible loop to a second, longer .alpha. helix. This structure binds both to DNA and to other HLH containing proteins. Dimer formation between RGTs permits a stronger binding to TCEs than would result from monomer binding. The LZ motif works in a similar way to strengthen the DNA binding capacity of two RGT monomers. LZ binding is characterized by the interaction of hydrophobic amino acids (usually leucine) extending from one side of the a helix of each monomer that permits them to dimerize forming a Y-shaped structure. The ends of the Y bind cooperatively to the TCE.
Several HLH proteins are truncated in the .alpha. helical region responsible for binding to DNA. These truncated HLH proteins act as negative regulators of other full-length HLH proteins by binding to them and forming inactive heterodimers. Mouse Id (inhibitor of DNA binding) binds to various HLH proteins (MyoD, E12, and E47) and inhibits their ability to bind to DNA and activate gene expression (Benezra, R. et al. (1990) 61:49-59). Vav is a novel oncogene expressed in cells of hematopoietic origin. Loss of the N-terminal HLH domain from a murine or human vav proto-oncogene activates its transforming potential. Katzav et al. (supra) suggest that this N-terminal region of 60-90 amino acids may act as a negative regulator of the expression of vav and possibly of other genes.
The discovery of a new regulator of gene transcription and the polynucleotides encoding it satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in the treatment or prevention of cancer and immune disorders.